Conventional Medical Management of Inflammatory Bowel Disease

Conventional therapies for ulcerative colitis and Crohn's disease (CD) include aminosalicylates, corticosteroids, thiopurines, methotrexate, and anti–tumor necrosis factor agents. A time-structured approach is required for appropriate management. Traditional step-up therapy has been partly replaced during the last decade by potent drugs and top-down therapies, with an accelerated step-up approach being the most appropriate in the majority of patients. When patients are diagnosed with CD or ulcerative colitis, physicians should consider the probable pattern of disease progression so that effective therapy is not delayed. This can be achieved by setting arbitrary time limits for administration of biological therapies, changing therapy from mesalamine in patients with active ulcerative colitis, or using rescue therapy for acute severe colitis. In this review, we provide algorithms with a time-structured approach for guidance of therapy. Common mistakes in conventional therapy include overprescription of mesalamine for CD; inappropriate use of steroids (for perianal CD, when there is sepsis, or for maintenance); delayed introduction or underdosing with azathioprine, 6-mercaptopurine, or methotrexate; and failure to consider timely surgery. The paradox of anti–tumor necrosis factor therapy is that although it too is used inappropriately (when patients have sepsis or fibrostenotic strictures) or too frequently (for diseases that would respond to less-potent therapy), it is also often introduced too late in disease progression. Conventional drugs are the mainstay of current therapy for inflammatory bowel diseases, but drug type, timing, and context must be optimized to manage individual patients effectively. Conventional therapies for ulcerative colitis and Crohn's disease (CD) include aminosalicylates, corticosteroids, thiopurines, methotrexate, and anti–tumor necrosis factor agents. A time-structured approach is required for appropriate management. Traditional step-up therapy has been partly replaced during the last decade by potent drugs and top-down therapies, with an accelerated step-up approach being the most appropriate in the majority of patients. When patients are diagnosed with CD or ulcerative colitis, physicians should consider the probable pattern of disease progression so that effective therapy is not delayed. This can be achieved by setting arbitrary time limits for administration of biological therapies, changing therapy from mesalamine in patients with active ulcerative colitis, or using rescue therapy for acute severe colitis. In this review, we provide algorithms with a time-structured approach for guidance of therapy. Common mistakes in conventional therapy include overprescription of mesalamine for CD; inappropriate use of steroids (for perianal CD, when there is sepsis, or for maintenance); delayed introduction or underdosing with azathioprine, 6-mercaptopurine, or methotrexate; and failure to consider timely surgery. The paradox of anti–tumor necrosis factor therapy is that although it too is used inappropriately (when patients have sepsis or fibrostenotic strictures) or too frequently (for diseases that would respond to less-potent therapy), it is also often introduced too late in disease progression. Conventional drugs are the mainstay of current therapy for inflammatory bowel diseases, but drug type, timing, and context must be optimized to manage individual patients effectively. View Large Image Figure ViewerDownload Hi-res image Download (PPT) We review conventional therapies for ulcerative colitis (UC) and Crohn's disease (CD), focusing on timing of treatment and specific dilemmas. Algorithms (Figure 1, Figure 2, Figure 3, Figure 4) are included for guidance, although treatment of patients is influenced by external factors such as comorbidities, drug intolerance, patient preferences, and the occupational context of the illness. In practice, treatment is also regulated by health care jurisdiction (certolizumab pegol, for example, is not licensed for the treatment of CD in Europe) or remuneration (especially for anti–tumor necrosis factor [TNF] therapy or steroids, such as budesonide). Detailed practice guidelines have been published in the United States, Asia, and Europe for UC and CD.1Kornbluth A. Sachar D.B. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee.Am J Gastroenterol. 2010; 105: 501-523Crossref PubMed Scopus (1014) Google Scholar, 2Travis S.P.L. Stange E.F. Lèmann M. et al.European evidence-based consensus on the management of ulcerative colitis: current management.J Crohns Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 3Ooi C.J. Fock K.M. Makharia G.K. et al.The Asia-Pacific consensus on ulcerative colitis.J Gastroenterol Hepatol. 2010; 25: 453-468Crossref PubMed Scopus (127) Google Scholar, 4Lichtenstein G.R. Hanauer S.B. Sandborn W.J. Management of Crohn's disease in adults.Am J Gastroenterol. 2009; 104 (quiz 464, 484): 465-483Crossref PubMed Scopus (725) Google Scholar, 5Dignass A. Van Assche G. Lindsay J.O. et al.The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management.J Crohns Colitis. 2010; 4: 28-62Abstract Full Text Full Text PDF PubMed Scopus (1224) Google Scholar In this article, conventional therapy means aminosalicylates, corticosteroids, thiopurines, methotrexate, and anti-TNF agents.Figure 1Management algorithm for mild-to-moderately active ulcerative colitis (UC). UC activity is defined as mild (≤4 motions/d) or moderate (≥4 bloody motions/d) when there are no signs of systemic toxicity (pulse <90 beats per minute, temperature <37.5°C, hemoglobin >10.5 g/dL, or erythrocyte sedimentation rate <30 mm/h). Oral 5-aminosalicylates include sulfasalazine 2–6 g daily, mesalamine 1.5–4.8 g daily, balasalazide 2–6.75 g daily, or olsalazine 1.5–3 g daily.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 2Management algorithm for acute severe ulcerative colitis (UC). Acute severe colitis is defined by Truelove and Witts' Criteria as ≥6 bloody stools/d in the presence of 1 or more of the following criteria: pulse of >90 beats per minute, temperature >37.8°C, hemoglobin <10.5 g/dL, or an erythrocyte sedimentation rate >30 mm/h.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Management algorithm for mild-to-moderate ileal Crohn's disease. Mild-to-moderate disease activity refers to intestinal inflammation in the absence of systemic symptoms (fevers, dehydration, and rigors), obstruction, painful mass, or >10% weight loss.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4Management algorithm for fistulizing perianal Crohn's disease. Simple fistulae do not involve the sphincter complex or branch to form multiple openings, and are not complicated by abscess formation, rectovaginal fistulization, or anal stricturing. The assessment modality is determined by local expertise.View Large Image Figure ViewerDownload Hi-res image Download (PPT) The choice of treatment depends on disease activity and extent, as well as patient acceptability and mode of drug delivery. Disease activity is best confirmed (and infection excluded) before therapy is initiated or when response to therapy is slow. To optimize conventional therapy, it is important to carefully time the steps of treatment and explain the strategy to the patient. 5-Aminosalicylates are the most common treatment for patients with mild (≤4 bloody stools/d) or moderately active disease (>4 bloody stools/d without systemic toxicity).6Ng S.C. Kamm M.A. Therapeutic strategies for the management of ulcerative colitis.Inflamm Bowel Dis. 2009; 15: 935-950Crossref PubMed Scopus (59) Google Scholar Absorption must be prevented to achieve colonic delivery, either by administration of a prodrug (balsalazide, olsalazine, or sulfasalazine), a drug with a gastroresistant, pH-dependent coating (eg, Asacol, Salofalk), or a drug with a slow-release mechanism (eg, Pentasa).7Lichtenstein G.R. Kamm M.A. Review article: 5-aminosalicylate formulations for the treatment of ulcerative colitis—methods of comparing release rates and delivery of 5-aminosalicylate to the colonic mucosa.Aliment Pharmacol Ther. 2008; 28: 663-673Crossref PubMed Scopus (61) Google Scholar Nevertheless, the asymmetrical, right-to-left gradient of drug delivery in the gastrointestinal tract means that only 9% of oral Asacol is delivered to the distal colon during active distal colitis.8Hebden J.M. Blackshaw P.E. Perkins A.C. et al.Limited exposure of the healthy distal colon to orally-dosed formulation is further exaggerated in active left-sided ulcerative colitis.Aliment Pharmacol Ther. 2000; 14: 155-161Crossref PubMed Scopus (80) Google Scholar Therefore, enemas or suppositories should be used to optimize mucosal concentrations of mesalamine in patients with distal UC.2Travis S.P.L. Stange E.F. Lèmann M. et al.European evidence-based consensus on the management of ulcerative colitis: current management.J Crohns Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar The best way to induce remission in patients with proctitis is with mesalamine suppositories because <10% of liquid and only 40% of foam from enemas remain in the rectum after 4 hours. Mesalamine suppositories (1 g/d) induced clinical remission in 64% patients with proctitis within 2 weeks.9Gionchetti P. Rizzello F. Venturi A. et al.Comparison of mesalazine suppositories in proctitis and distal proctosigmoiditis.Aliment Pharmacol Ther. 1997; 11: 1053-1057Crossref PubMed Scopus (52) Google Scholar For patients who do not respond to topical mesalamine, a combination of topical corticosteroid and mesalamine leads to better clinical, endoscopic, and histological improvements than either drug alone.2Travis S.P.L. Stange E.F. Lèmann M. et al.European evidence-based consensus on the management of ulcerative colitis: current management.J Crohns Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar Other topical therapies (eg, arsenic, lidocaine) can be used, more in hope than with expectation.2Travis S.P.L. Stange E.F. Lèmann M. et al.European evidence-based consensus on the management of ulcerative colitis: current management.J Crohns Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar Oral corticosteroids are often used, but there have been no clinical trials of prednisone for isolated proctitis. In a review of 420 patients treated with infliximab for UC, 13 of 420 had refractory proctitis; 11 of 13 responded to infliximab and 9 of 11 maintained response during a median 17 months.10Bouguen G. Roblin X. Bourreille A. et al.Infliximab for refractory ulcerative proctitis.Aliment Pharmacol Ther. 2010; 31: 1178-1185Crossref PubMed Scopus (28) Google Scholar For distal or left-sided colitis, rectal mesalamine is better than steroids for inducing remission (odds ratio = 1.65).11Marshall J.K. Thabane M. Steinhart A.H. et al.Rectal 5-aminosalicylic acid for induction of remission in ulcerative colitis.Cochrane Database Syst Rev. 2010; (CD004115)Google Scholar The combination of oral and rectal mesalamine is better at stopping rectal bleeding (89%) than rectal (69%) or oral (46%) monotherapy.12Safdi M. DeMicco M. Sninsky C. et al.A double-blind comparison of oral versus rectal mesalamine versus combination therapy in the treatment of distal ulcerative colitis.Am J Gastroenterol. 1997; 92: 1867-1871PubMed Google Scholar Sulfasalazine cannot be justified as a first-line therapy because of side effects, although mesalamine drugs are no more effective than sulfasalazine (odds ratio = 0.83), yet are 4-fold the price.13Sutherland L. Macdonald J.K. Oral 5-aminosalicylic acid for induction of remission in ulcerative colitis.Cochrane Database Syst Rev. 2006; (CD000543)Google Scholar Combining oral mesalamine (4 g) with enemas (1 g) is better than oral monotherapy for mild-to-moderately active, extensive UC—the combination induces 64% remission within 8 weeks, compared to 43% with oral monotherapy.14Marteau P. Probert C.S. Lindgren S. et al.Combined oral and enema treatment with Pentasa (mesalazine) is superior to oral therapy alone in patients with extensive mild/moderate active ulcerative colitis: a randomised, double blind, placebo controlled study.Gut. 2005; 54: 960-965Crossref PubMed Scopus (278) Google Scholar This combination is appropriate for initial therapy as long as there is no delay in escalating treatment for slow responders. Oral mesalamine without enemas is generally preferred by patients with active UC and can work rapidly. Median time to cessation of rectal bleeding in patients with moderately active UC treated with mesalamine was 9 days for 4.8 g/d and 16 days for 2.4g/d.15Orchard T.R. van der Geest S.A. Travis S.P. Randomised clinical trial: early assessment after 2 weeks of high-dose mesalazine for moderately active ulcerative colitis - new light on a familiar question.Aliment Pharmacol Ther. 2011; (Mar 8 [Epub ahead of print])Google Scholar This can guide the time to escalate therapy; if rectal bleeding persists after 10–14 days, then patients are slow responders to mesalamine and treatment escalation is generally appropriate.2Travis S.P.L. Stange E.F. Lèmann M. et al.European evidence-based consensus on the management of ulcerative colitis: current management.J Crohns Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar Alternative strategies of waiting 3–4 weeks to escalate therapy in those with relatively mild symptoms, or simply increasing the dosage of mesalamine at 10–14 days and waiting an additional 14 days before committing to steroids are also reasonable, but the decision depends on the views of the patient. The optimal starting dosage of prednisone is 40 mg/d; higher dosages increase side effects with limited therapeutic gain. No randomized trials have compared tapering regimes, but most physicians reduce the dosage by 5 mg each week. However, of 84% patients who initially responded to steroids (remission rate 54%), only 49% were steroid- and surgery-free 1 year later.16Faubion Jr, W.A. Loftus Jr, E.V. Harmsen W.S. et al.The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study.Gastroenterology. 2001; 121: 255-260Abstract Full Text Full Text PDF PubMed Scopus (1002) Google Scholar Moving straight from mesalamine to infliximab is an effective option that avoids steroids; 33.9% of patients achieved remission after 8 weeks of therapy with 5 mg/kg infliximab, compared with 5.7% given placebo.17Rutgeerts P. Sandborn W.J. Feagan B.G. et al.Infliximab for induction and maintenance therapy for ulcerative colitis.N Engl J Med. 2005; 353: 2462-2476Crossref PubMed Scopus (3033) Google Scholar However, infliximab is generally reserved for those who do not respond to or cannot tolerate steroids.1Kornbluth A. Sachar D.B. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee.Am J Gastroenterol. 2010; 105: 501-523Crossref PubMed Scopus (1014) Google Scholar, 2Travis S.P.L. Stange E.F. Lèmann M. et al.European evidence-based consensus on the management of ulcerative colitis: current management.J Crohns Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar Acute severe UC is defined as a bloody stool frequency ≥6/d and a tachycardia (>90 beats per minute), temperature >37.8°C, anemia (hemoglobin <10.5 g/dL), or an increased erythrocyte sedimentation rate (>30 mm/hr).1Kornbluth A. Sachar D.B. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee.Am J Gastroenterol. 2010; 105: 501-523Crossref PubMed Scopus (1014) Google Scholar, 2Travis S.P.L. Stange E.F. Lèmann M. et al.European evidence-based consensus on the management of ulcerative colitis: current management.J Crohns Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar Flexible sigmoidoscopy is used to confirm active disease and exclude cytomegalovirus infection,18Ayre K. Warren B. Jeffery K. et al.The role of CMV in steroid-resistant ulcerative colitis: a systematic review.J Crohns Colitis. 2009; 3: 141-148Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar along with stool sample analysis for Clostridium difficile toxin and plain abdominal radiography to exclude colon dilatation. Administration of intravenous corticosteroids (methylprednisolone 60 mg or equivalent) should not be delayed while waiting for results from microbiology testing. Higher dosages are no more effective, but lower dosages are less effective.2Travis S.P.L. Stange E.F. Lèmann M. et al.European evidence-based consensus on the management of ulcerative colitis: current management.J Crohns Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar Fluid and electrolyte replacement, with heparin thromboprophylaxis, are considered to be essential, but neither intravenous nutrition nor antibiotics have altered outcomes in controlled trials.2Travis S.P.L. Stange E.F. Lèmann M. et al.European evidence-based consensus on the management of ulcerative colitis: current management.J Crohns Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar C difficile infection is associated with worse outcomes in patients hospitalized with UC. Based on the Nationwide Inpatient Sample, the prevalence of C difficile in patients with UC (37.3/1000) was 3-fold higher than in those with CD (10.9/1000), was associated with greater mortality (odds ratio = 3.79), and resulted in a 65% longer length of hospital stay.19Nguyen G.C. Kaplan G.G. Harris M.L. et al.A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients.Am J Gastroenterol. 2008; 103: 1443-1450Crossref PubMed Scopus (303) Google Scholar Oral dosages of vancomycin should be given if C difficile infection is suspected. The response to corticosteroids has remained unchanged for decades: in 32 trials involving 1991 patients from 1974 to 2006, the overall response was 67%; 29% required colectomies.20Turner D. Walsh C.M. Steinhart A.H. et al.Response to corticosteroids in severe ulcerative colitis: a systematic review of the literature and a meta-regression.Clin Gastroenterol Hepatol. 2007; 5: 103-110Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar Treatment is usually given for about 5 days; extending therapy beyond 7 days has no benefit. Response is best assessed objectively around the third day. Among patients with stool frequencies of 3–8/d and levels of C-reactive protein (CRP) >45 mg/L on the third day of intravenous steroids, 85% needed colectomies.21Travis S.P.L. Satsangi J. Lèmann M. Predicting the need for colectomy in severe UC: a critical appraisal of clinical parameters and currently available biomarkers.Gut. 2011; 60: 3-9Crossref PubMed Scopus (63) Google Scholar Surgical options are best considered and discussed at this stage, although “rescue” therapy with either cyclosporine or infliximab is often appropriate. Preliminary results from a randomized controlled trial that compared the effects of cyclosporin and infliximab in 110 patients showed no difference in short-term (7- and 90-day) efficacy.22Laharie D. Bourreille A. Branche J. et al.Ciclospirin and infliximab for acute severe colitis failing intravenous steroids: a randomised controlled trial.J Crohns Colitis. 2011; 5: S8Google Scholar A randomized study of 45 patients demonstrated the efficacy of infliximab—24 patients were given 5 mg/kg infliximab and 21 were given placebo with continued intravenous betamethasone; 7 of 24 in the infliximab group and 14 of 21 in the placebo group needed a colectomy within 3 months (odds ratio = 4.9).23Jarnerot G.G. Hertervig E.E. Friis-Liby I.I. et al.Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study.Gastroenterology. 2005; 128: 1805-1811Abstract Full Text Full Text PDF PubMed Scopus (915) Google Scholar The difference in outcomes between groups was maintained during 3 years (12 of 24 required a colectomy after infliximab treatment vs 16/21 after placebo), although most patients received a single dose of infliximab.24Gustavsson A. Jarnerot G. Hertervig E. et al.Clinical trial: colectomy after rescue therapy in ulcerative colitis - 3-year follow-up of the Swedish-Danish controlled infliximab study.Aliment Pharmacol Ther. 2010; 32: 984-989Crossref PubMed Scopus (143) Google Scholar In the largest randomized study of cyclosporin, 73 patients received either 2 mg/kg or 4 mg/kg; response rates were similar between groups at 8 days (86% and 84%, respectively); 9% required a colectomy in the 2 mg/kg group and 13% in the 4 mg/kg group. In patients given 2 mg/kg, the mean cyclosporin concentration on day 4 was 246 ± 64 ng/mL, but in patients given 4 mg/kg, it was 345 ± 146 ng/mL.25Van Assche G. D'Haens G. Noman M. et al.Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis.Gastroenterology. 2003; 125: 1025-1031Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar Most of cyclosporin's side effects were dose-dependent, so low-dose (2 mg/kg) intravenous induction is the best option. Many gastroenterologists are more familiar with infliximab than cyclosporin, but the short half-life of cyclosporin is a potential advantage if infliximab does not work—cyclosporin disappears from the circulation within hours, whereas infliximab circulates for weeks. This could matter if emergency colectomy is necessary because septic complications cause most postoperative morbidity.26Lees C.W. Heys D. Ho G.T. et al.A retrospective analysis of the efficacy and safety of infliximab as rescue therapy in acute severe ulcerative colitis.Aliment Pharmacol Ther. 2007; 26: 411-419Crossref PubMed Scopus (113) Google Scholar Although steroids (but not infliximab) increased the risk of postoperative infection in one study (odds ratio = 5.19 for ≥20 mg methylprednisolone for ≥2 months), 137 of 141 had elective rather than emergency colectomies, so the safety of infliximab in this context is unresolved.27Ferrante M. D'Hoore A. Vermeire S. et al.Corticosteroids but not infliximab increase short-term postoperative infectious complications in patients with ulcerative colitis.Inflamm Bowel Dis. 2009; 15: 1062-1070Crossref PubMed Scopus (205) Google Scholar The median time to response for cyclosporin is 4 days, based on decreases in stool frequency and levels of CRP—this time is similar to that for infliximab.25Van Assche G. D'Haens G. Noman M. et al.Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis.Gastroenterology. 2003; 125: 1025-1031Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar Colectomy is recommended if there is clinical deterioration or no improvement within 4–7 days of rescue therapy.1Kornbluth A. Sachar D.B. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee.Am J Gastroenterol. 2010; 105: 501-523Crossref PubMed Scopus (1014) Google Scholar, 2Travis S.P.L. Stange E.F. Lèmann M. et al.European evidence-based consensus on the management of ulcerative colitis: current management.J Crohns Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar, 21Travis S.P.L. Satsangi J. Lèmann M. Predicting the need for colectomy in severe UC: a critical appraisal of clinical parameters and currently available biomarkers.Gut. 2011; 60: 3-9Crossref PubMed Scopus (63) Google Scholar Contingency planning to prepare for surgery allows time for rescue therapy to work within the bounds of safety. The worst outcome is not surgery, but the mortality associated with acute severe UC.28Nguyen G.C. Prather C.M. Is keeping the colon the ultimate marker of success in ulcerative colitis?.Gastroenterology. 2009; 137: 1204-1206Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar Treatment-refractory UC can be severe in terms of consequences for the patient, but should be distinguished from acute severe UC. For patients with treatment-refractory UC, the disease activity should be confirmed, adherence to treatment evaluated, other causes of persistent symptoms considered (including proximal constipation, defecation disorder, mucosal prolapse, or cancer), and the pattern of disease progression reviewed.1Kornbluth A. Sachar D.B. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee.Am J Gastroenterol. 2010; 105: 501-523Crossref PubMed Scopus (1014) Google Scholar, 2Travis S.P.L. Stange E.F. Lèmann M. et al.European evidence-based consensus on the management of ulcerative colitis: current management.J Crohns Colitis. 2008; 2: 24-62Abstract Full Text Full Text PDF PubMed Scopus (509) Google Scholar Patients with corticosteroid-dependence who are unable to withdraw prednisolone within 3 months of starting, or relapse within 3 months of stopping steroids, should receive therapy with thiopurines. When azathioprine was given to 156 patients with UC, the rate of steroid dependence decreased from 39% to 9%.29Gisbert J.P. Nino P. Cara C. et al.Comparative effectiveness of azathioprine in Crohn's disease and ulcerative colitis: prospective, long-term, follow-up study of 394 patients.Aliment Pharmacol Ther. 2008; 28: 228-238Crossref PubMed Scopus (63) Google Scholar Treatment with infliximab is also appropriate. A Cochrane review analyzed 7 placebo-controlled trials of UC that was refractory to steroids and/or immunomodulators; infliximab was more effective than placebo for inducing clinical (relative risk: 3.22) and endoscopic remission (relative risk: 1.9) at 8 weeks.30Lawson M.M. Thomas A.G. Akobeng A.K. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis.Cochrane Database Syst Rev. 2006; 3 (CD005112)PubMed Google Scholar A primary response to infliximab occurred in 78% of 191 patients with UC in a French multicenter study.31Oussalah A. Evesque L. Laharie D. et al.A multicenter experience with infliximab for ulcerative colitis: outcomes and predictors of response, optimization, colectomy, and hospitalization.Am J Gastroenterol. 2010; 105: 2617-2625Crossref PubMed Scopus (157) Google Scholar Adalimumab is also effective for treatment-refractory UC; 18.5% of patients went into remission and 54.6% responded to 8 weeks of therapy with 160 or 80 mg adalimumab (followed by 40 mg adalimumab every other week), compared with 9.2% that went into remission and 44.6% that responded to placebo.32Reinisch W. Sandborn W.J. Hommes D. et al.Adalimumab for induction of remission in moderately to severely active ulcerative colitis: results of a randomized controlled trial.Gut. 2011 Jan 5; ([Epub ahead of print])Google Scholar Why these remission rates appear lower than in the ACT 1 (Ulcerative Colitis Treatment) trial is unclear; it may be that the dosage of adalimumab was too low, duration of therapy too short, or a consequence of variability in the scoring of endoscopy or physician's global assessment.33Travis S. Does it all ADA up? Adalimumab for ulcerative colitis.Gut. 2011 Jan 21; ([Epub ahead of print])Google Scholar The therapeutic strategies are broadly similar in CD and UC, although significant differences exist, including a limited or lack of response to mesalamine or cyclosporin, response to nutritional therapy, and greater need for surgery in CD.4Lichtenstein G.R. Hanauer S.B. Sandborn W.J. Management of Crohn's disease in adults.Am J Gastroenterol. 2009; 104 (quiz 464, 484): 465-483Crossref PubMed Scopus (725) Google Scholar, 5Dignass A. Van Assche G. Lindsay J.O. et al.The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management.J Crohns Colitis. 2010; 4: 28-62Abstract Full Text Full Text PDF PubMed Scopus (1224) Google Scholar Enthusiasm for biological therapy needs to be tempered with recognition that half will have a benign course; in a Norwegian, 10-year, population-based study, just 53% developed stricturing or penetrating disease.34Solberg I.C. Vatn M.H. Hoie O. et al.Clinical course in Crohn's disease: results of a Norwegian population-based ten-year follow-up study.Clin Gastroenterol Hepatol. 2007; 5: 1430-1438Abstract Full Text Full Text PDF PubMed Scopus (528) Google Scholar At diagnosis, it is possible to identify patients with poor prognosis. In a study of 371 patients in Belgium, 37% developed complex perianal disease, colonic resection, ≥2 small bowel resections, or a definitive stoma within 5 years.35Loly C. Belaiche J.